About 30,000 North Americans have rupture of an intracranial aneurysm each year. Because aneurysmal rupture, among all forms of intracranial bleeding, almost uniquely deposits a large volume of blood clot on the adventitial side of the basal conducting arteries, it is frequently the cause of a delayed onset, long-lasting arterial constriction known as vasospasm. Vasospasm can be so severe that the vessels may actually be occluded and distal ischemia can result with attendant delayed infarction - the second stroke. About two-thirds of ruptured aneurysm patients will show moderate to severe degrees of angiographic vasospasm if subjected to angiography a week or so after the initial hemorrhage. About half of these patients will develop clinical signs of delayed ischemia. The death rate from this phenomenon has fallen steadily in recent years with the widespread avoidance of dehydration and antifibrinolytic agents. In addition, calcium antagonists, hypertension and hypervolemia may have exerted a beneficial effect. Currently, however, about 15% of patients will still die or be severely damaged by vasospasm. Evidence of ischemic cerebral infarction is noted in about 30% of the fatal cases of aneurysmal ruptures if they survive past the initial few days. Our long-term objectives are: (1) prevention of vasospasm after subarachnoid hemorrhage; (2) the successful treatment of established vasospasm. The specific aims of the project are to determine: (1) time course of cytoskeletal changes in arterial walls of cerebral arteries after subarachnoid hemorrhage in monkeys; (2) pathogenesis and prevention of oxyhemoglobin-induced cerebral vasospasm in monkeys; (3) biochemical changes in arterial vessel wall as vasospasm develops and abates; (4) time course of intracellular free calcium concentration changes in cultured vascular smooth muscle cells following prolonged exposure to oxyhemoglobin and if the mechanism of calcium entry is sensitive to normal antagonists of calcium channels; (5) role of activation of protein kinase C in production of cerebrovascular spasm; (6) the source of increased intracellular calcium correlated with damage by oxyhemoglobin; (7) if free radicals damage isolated cerebrovascular smooth muscle cells primarily from the inside or outside; (8) whether free radicals damage lipid components of surface membrane or ion channels; (9) if transluminal balloon dilatation of spastic primate cerebral arteries results in immediate and enduring improvement in vessel caliber and whether there is any adverse structural change in the arterial wall; (10) if intrathecal urokinase can prevent chronic cerebral vasospasm in a primate model.